Role of Calprotectin in Withholding Zinc and Copper from Candida albicans Original paper

What was studied?

This original study tested the Role of calprotectin in withholding zinc and copper from Candida albicans and defined when this host protein blocks metal nutrition to shape fungal survival. The authors asked if calprotectin (the S100A8/S100A9 complex) depletes bioavailable Zn and Cu around the fungus, how C. albicans adapts its metal uptake systems, and whether these responses occur in vivo during kidney infection. They measured fungal growth, intracellular metals, and metal-stress transcripts in vitro under yeast extract medium and serum conditions, and then tracked the same signatures in a mouse model of disseminated candidiasis to map the timing of Zn and Cu stress in tissue.

Who was studied?

The work used Candida albicans strain SC5314 and isogenic mutants in the Zn-stress regulator Zap1, with recombinant human calprotectin variants that either bind metals or cannot bind metals. The team grew yeast in rich medium and in 50% serum to capture host-like metal sources, quantified intracellular Zn, Cu, Mn by ICP-MS, and profiled transcripts of Zn uptake genes (ZRT1, PRA1) and Cu-stress enzymes (SOD1, SOD3). They then infected wild-type mice and calprotectin-deficient S100A9−/− mice, sampled kidneys over 24–72 hours, and measured host metals and fungal metal-stress transcripts to define how calprotectin shapes Zn and Cu availability early in infection.

Most important findings

Calprotectin bound metals with very high affinity and removed Zn from medium, which drove strong induction of C. albicans ZRT1 and PRA1 and held intracellular Zn steady through several divisions despite severe extracellular depletion; Zap1 loss increased calprotectin toxicity, and Zn supplementation reversed growth arrest, proving Zn withholding as the main stressor. In serum, calprotectin also withheld Cu: it blocked fungal acquisition of serum Cu, induced the classic Cu-sparing switch with SOD1 down and SOD3 up, and modestly increased CTR1, consistent with a Cu-starvation response.

Competition assays showed sub-picomolar Cu(II) binding at both calprotectin metal sites, explaining direct Cu sequestration. In vivo, kidney infection revealed distinct time courses: Zn-starvation markers (ZRT1, PRA1) spiked at 24 hours and depended on calprotectin, then faded by 72 hours as total kidney Zn rose; Cu-starvation markers (SOD1 down, SOD3 up) developed across 24–72 hours and did not require calprotectin at late timepoints, matching a fall in total kidney Cu that was calprotectin-independent. Together these data define a microbiome signature of early calprotectin-driven Zn withholding plus a broader, evolving Cu-limitation program in kidney tissue.

Key implications

Clinicians can read calprotectin as an early metal gatekeeper that restricts Zn and, in serum-rich niches, Cu, reshaping fungal metabolism and fitness. In a microbiome signatures database, pair calprotectin exposure with acute C. albicans ZRT1/PRA1 induction and the Cu-sparing SOD1→SOD3 switch, and note the temporal split: calprotectin drives early Zn stress, while kidney Cu limitation expands over time via additional host routes. These markers help judge risk for dissemination and guide supportive steps that avoid unintended metal supplementation in serum or devices. They also highlight why metal content and pH of local fluids, and neutrophil influx that delivers calprotectin, can tip colonization toward or away from invasive disease.